Pancreatitis is the most frequent complication of endoscopic retrograde cholangiopancreatography (ERCP), accounting for substantial morbidity, occasional mortality, and increased health care expenditures. Many pharmacologic agents have been studied in the prevention of post-ERCP pancreatitis (PEP), however clinical trial results have been disappointing either due to inadequate sample sizes or absence of benefit. Recently, several studies evaluating the protective effect of non-steroidal anti- inflammatory drugs (NSAIDs) have been published. Our recently reported meta-analysis suggests substantial benefit. Definitive prospective clinical data, however, are necessary to impact current clinical practice. Objective: To determine the feasibility of establishing a multi-center clinical trial to study the efficacy of prophylactic rectally-administered indomethacin on the incidence of post-ERCP pancreatitis in high risk patients. Methods: The study is designed as a multi-center, prospective, randomized, placebo-controlled, double-blind clinical trial, enrolling a total 948 consecutive high risk patients undergoing ERCP. High risk subjects will be selected on the basis of validated patient and procedure-related risk factors. Enrolled subjects will be randomized to receive either placebo or indomethacin suppositories at the time of ERCP. Patient and procedure characteristics will be recorded at the time of the ERCP. Study outcomes, including the presence and severity of post-ERCP pancreatitis, will be collected within 5 days and at 30 days after the procedure. For analysis of the primary endpoint, the difference in the proportion of patients developing post-ERCP pancreatitis between the indomethacin group and placebo group will be analyzed using a two-tailed Fisher's exact test. Our objective during the funding period is to establish, at two medical centers, the necessary study infrastructure that can ultimately be extended to additional centers to successfully complete this pivotal clinical trial. Our target is to accrue 256 subjects within 16 months into the pilot funding period, allowing for an interim analysis (along with existing subject data), the results of which will be used to apply for additional funding. Significance: If positive, the results of this definitive clinical trial will immediately impact clinical practice by supporting the widespread use of prophylactic indomethacin at the time of ERCP. This may result in a substantial reduction of procedure-related morbidity as well as healthcare cost savings in excess of $75,000,000 annually in the United States. A negative study would also be beneficial by providing an answer to this critically important clinical question and setting the standard by which future trials of pharmacoprevention in PEP should be conducted. The R21 pilot and feasibility grant will serve to fund the pilot phase of this definitive clinical trial, during which the feasibility of this study will be determined and infrastructure adjustments will be made. PUBLIC HEALTH RELEVANCE: Pancreatitis, or inflammation of the pancreas, is the most common and devastating complication of endoscopic retrograde cholangiopancreatography (ERCP), an important diagnostic and therapeutic procedure. An effective way of preventing pancreatitis after ERCP would be highly beneficial, both from clinical and economic standpoints. Based on substantial preliminary data, we believe that a single dose of a widely available anti- inflammatory drug, indomethacin, given at the time of ERCP will be effective in preventing pancreatitis after ERCP. The objective of this study is to set up an infrastructure of medical centers that can determine, in a scientifically rigorous fashion, if indomethacin reduces the risk of pancreatitis after ERCP.